Case Report in JCO, Precision Oncology

Clinical detection of sequence and structural variants in known cancer genes points to viable treatment options for a minority of children with cancer.1 To increase the number of children who benefit from genomic profiling, gene expression information must be considered alongside mutations.2,3 Although high expression has been used to nominate drug targets for pediatric cancers,4,5 its utility has not been evaluated in a systematic way.6 We describe a child with a rare sarcoma that was profiled with whole-genome and RNA sequencing (RNA-Seq) techniques. Although the tumor did not harbor DNA mutations targetable by available therapies, incorporation of gene expression information derived from RNA-Seq analysis led to a therapy that produced a significant clinical response. We use this case to describe a framework for inclusion of gene expression into the clinical genomic evaluation of pediatric tumors.

Patient 1 was diagnosed at 8 years of age with a left tentorial-based CNS sarcoma after a 2-week history of nausea, lethargy, and diplopia. Clinical workup confirmed that the tumor was primary to the brain (Figs 1A and 1B). Histology revealed a mitotically active, epithelioid-to-spindled cell tumor in patternless sheets, interrupted by thick fibrous bands and foci of necrosis (Figs 1C to 1D). Immunohistochemistry revealed diffuse positivity for vimentin, desmin, neuron-specific enolase, epithelial membrane antigen, and CD99 (Figs 1E to 1H). Focal immunohistochemical positivity was observed for pan-cytokeratin (AE1/AE3) and synaptophysin. The tumor was negative for glial fibrillary acidic protein (GFAP), Wilms tumor 1 (WT1), myo-D1, myogenin, smooth muscle actin, nonphosphorylated and phosphorylated neurofilament protein, CD34, CD31, HMB-45, S-100, leukocyte common antigen, and BAF47/INI-1 (retained nuclear positivity). The Ki67 proliferative index was 9%. A diagnosis of desmoplastic small round cell tumor (DSRCT) was favored initially.7 Because EWSR1 breakapart fluorescence in situ hybridization confirmed an EWSR rearrangement but concomitant WT1 breakapart fluorescence in situ hybridization was negative, the molecular criterion for DSRCT was not met, and a final diagnosis of poorly differentiated sarcoma, not otherwise specified, was rendered. The patient received six cycles of induction chemotherapy—ifosfamide, carboplatin, and etoposide—followed by autologous stem-cell transplantation with a high-dose preparative regimen of carboplatin, thiotepa, and etoposide as well as 54 Gy of focal radiation to the location of the original tumor. After a 2-year remission, the tumor recurred with numerous pulmonary lesions in all lobes. The histologic characteristics of the metastasis were identical to the primary tumor. The patient enrolled in the Personalized OncoGenomics (POG)3 study, which offers whole-genome sequencing (WGS) and transcriptome sequencing and analysis to identify drivers and potential therapeutic options of relapsed solid tumors for children and adults in British Columbia.

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